Diphenyl methane laxatives do not induce electrolyte imbalance

doi:10.4236/ojgas.2013.35046

Paper Menu >>

Journal Menu >>

Open Journal of Gastroenterology, 2013, 3, 272-275 OJGas

http://dx.doi.org/10.4236/ojgas.2013.35046 Published Online September 2013 (http://www.scirp.org/journal/ojgas/)

Diphenyl methane laxatives do not induce electrolyte

imbalance

Stefan Müller-Lissner

Department of Internal Medicine, Park-Klinik Weissensee, Schönstrasse, Berlin

Email: [email protected]

Received 2 July 2013; revised 5 August 2013; accepted 18 August 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Aim: To analyse whether there are changes in sodium

and potassium serum levels during chronic treatment

with the diphenyl methanes bisacodyl and sodium

picosulfate. Methods: A literature search was done

using PubMed, and the reference lists of pertinent

papers were screened for additional studies. Only

studies of at least 4 weeks duration were considered

for further analysis. Results: Four relevant studies

were identified. In three randomised controlled trials

with 5 to 10 mg daily of bisacodyl or sodium picosul-

fate, respectively, over four weeks no electrolyte losses

were found. Hypokalemia was also not a problem in a

group of patients with paraplegia using bisacodyl

suppositories for 2 to 34 years. Conclusions: Electro-

lyte losses, particularly hypokalemia, are not a prob-

lem when bisacodyl or sodium picosulfate are used

long-term.

Keywords: Laxative; Bisacodyl; Sodium Picosulfate;

Hyponatremia; H ypokalemia

1. INTRODUCTION

Consumer reports, whether printed or in the internet,

often contain warnings of side effects of laxatives, par-

ticularly of the so-called stimulan t laxatives. These com-

prise the anthraquinones (e.g. sennosides) and the di-

phenyl methane derivatives (bisacodyl and sodium pico-

sulfate) and exert a dual, namely a secretory and a pro-

kinetic action [1,2]. These warnings read e.g. “confusion,

irregular heartbeat, muscle cramps, and unusual tiredness

or weakness” [3-6 ].

Similar concerns have, to my knowledge, not been ex-

pressed regarding water binding laxatives (salinic laxa-

tives, sugars such as lactulose, and macrogol). Nor have

they been expressed for pure prokinetics such as pruca-

lopride and the new secretory stimulants lubiprostone

and linaclotide, potentially because the manufacturers

were hitherto successful in avoiding the term “laxative”

for these products.

If these side effects would occur they would occur with

almost certainty be due to electrolyte losses, particularly

of potassium. It is well known that induction of diarrhea

by these laxatives may lead to hypokalemia [7-9], but

this does not allow the conclusion that such losses may

also occur when the laxatives are used in the proper dose.

The purpose of the present paper is to present the

available data of sodium and potassium serum levels dur-

ing chronic treatment of chronic constipation with di-

phenyl methanes.

2. METHODS

A literature search was done using PubMed with the

terms (diphenyl methanes OR bisacodyl OR sodium pi-

cosulfate) AND (electrolytes OR sodium OR potassium)

and the available respective MeSH terms (“picosulfate

sodium” [Supplementary Concept]) AND (“Hypokale-

mia” [Mesh] OR “Water-Electrolyte Imbalance” [Mesh]).

In addition the reference lists of the papers were screened

for additional studies. Only studies of at least 4 weeks

duration were considered for further analysis. The manu-

facturer of bisacodyl and sodium picosulfate was then

asked to provide the original data on electrolytes from

the respective trials.

3. RESULTS

The oldest paper on the subject reports long-term data

from 101 patients with spinal cord injury using bisacodyl

over a period of 2 to 34 years. Patients used bisacodyl

suppositories, predominantly one to two suppositories

two or three times weekly [10]. Only two patients had

potassium levels slightly below the lower limit of nor-

mality and without clinical relevance (Figure 1). How-

ever, no information is available regarding intake of

other drugs affecting serum electrolytes such as diuretics.

There are three randomised controlled trials with

OPEN ACCESS

S. Müller-Lissner / Open Journal of Gastroenterology 3 (2013) 272-275 273

Figure 1. Serum potassium levels in 88 paraplegic patients

chronically using bisacodyl suppositories. More than 80% of

the patients used bisacodyl for more than 5 years. Shaded area:

normal range. Data from 10.

orally administered diphenyl methanes over 4 weeks

each in patients with chronic constipation according to

the Rome II and Rome III criteria, respectively [11,12].

After a one to two weeks baseline period, patients were

randomized to one of two arms.

In the first open-label study, bisacodyl 5 to 10 mg was

compared to 5 to 10 mg sodium picosulfate daily in 144

patients [13]. There was no difference regarding efficacy

between both drugs, and there were no losses of electro-

lytes as shown in Figure 2(A).

The second study compared bisacodyl 5 to 10 mg to

placebo in 368 patients [14], and the third study com-

pared sodium picosulfate 5 to 10 mg to placebo in 367

patients [15]. As expected, active treatments were largely

superior to placebo. Figures 2(B) and (C) show the time

course of serum sodium and potassium in these double-

blind trials. Again, hypokalemia or hyponatremia did not

occur.

The designs of these trials are summarized in Table 1,

baseline characteristics of their patients are given in Ta-

ble 2.

130

140

150

mmo l/l

3.5

4.5

5.5

baseline final

mmol/l

bisacodyl SPS

130

140

150

mmo l/l

3.5

4.5

5.5

baselinefinal

mmo l/l

bisacodyl placebo

130

140

150

mmo l/l

3.5

4.5

5.5

baseline final

mmol/l

SPS placebo

sodium

potassiu m

ABC

Figure 2. Serum levels of sodium and potassium at the beginning and end of tre atme nt with bisacodyl, sodium picosulfate (SPS), and

placebo, respectively, for 4 weeks (means ± SD). Shaded area: normal range. (A) from Ref. [13]; (B) from Ref. [14]; (C) from Ref.

[15].

Table 1. Characteristics of published studies with bisacodyl or sodium picosulfate in chronically constipated patients giving details

on serum electrolyte s. SPS: sodium pic osulfa te .

Number of

patients Treatment arm 1 Treatment arm 2 Duration Reference

88 1 to 2 bisacodyl suppositories

2 to 3 times weekly None 2 to 34 years [10]

144 Bisacodyl 5 to 10 mg daily 5 to 10 mg SPS daily 4 weeks [13]

368 Bisacodyl 5 to 10 mg daily Placebo 4 weeks [14]

367 SPS 5 to 10 mg daily placebo 4 weeks [15]

S. Müller-Lissner / Open Journal of Gastroenterology 3 (2013) 272-275

274

Table 2. Baseline data from studies with bisacodyl or sodium picosulfate in chronically constipated patients giving details on serum

electrolytes. SPS: sodium picosulfate.

Reference [13] [14] [15]

Number of patients on bisacodyl 70 247 -

Number of patients on SPS 74 - 233

Number of patients on placebo - 121 134

Number of females (n, %) 104 (67.5) 275 (74.7) 285 (77.7)

Age (years, s.d.) 62.7 (18.3) 55.4 (15.6) 50.8 (16.9)

Duration of constipation (years, s.d.) >6 months 21.2 (19.2) 13.2 (14.0)

Baseline stool frequency (per week, s.d.) 3.2 (1.2) 4.2 (1.1) 3.1 (1.1)

There were no differences regarding sex distribution, age, duration of constipation, and baseline stool frequency between the treatment groups within the three

trials.

4. DISCUSSION

The role of the colon is threefold, namely absorbing wa-

ter from intestinal contents, retaining, mixing and pro-

pelling feces, and allowing bacterial degradation of un-

digested nutrients such as dietary fiber. The latter con-

siderably contributes to the energy balance of species

with a large cecum such as rodents but is of minor im-

portance in man. About 2 liters of small intestinal juice

enter the colon each day being reduced to around 200 ml

of more or less solid feces. However, in diarrheal states

large amounts of fluids may be excreted. This fluid con-

tains electrolytes in concentrations isoosmotic to serum.

This holds true for both osmotic and secretory diarrhea.

Both anthraquinones and diphenyl methanes may induce

diarrhea when given in too high doses. This is a well

known effect in psychiatric patients abusing laxatives

such as anorexia nervosa or Munchhausen’s syndrome

[7-9,16]. Under these circumstances hypokalemia is the

most prominent and dangerous laboratory abnormality

potentially causing muscle weakness and kidney injury.

However, these psychiatric conditions definitely differ

from chronic laxative intake for constipation, e.g. since

the laxative intake is concealed by the users.

Diarrhea is the desired effect if laxatives are used in

bowel cleansing protocols. However, such protocols to-

day usually contain macrogol alone or in combination

with another laxative such as bisacodyl. Macrogol pre-

parations for bowel cleansing contain however electro-

lytes in isoosmotic concentration in order to prevent

electrolyte from shifting from blood to the colonic lumen.

Therefore, data from studies on bowel preparation are

not likely to show potential electro lyte losses induced by

bisacodyl and are not suited to refute such a side effect.

Rather the analysis had to focus on trials with one secre-

tory laxative only.

Since chronic constipation usually requires long-term

laxative intake, only studies of several weeks duration

were considered for further analysis. In addition, it is al-

ready known that short time treatment with bisacodyl or

sodium picosulfate does not affect serum electrolytes

[17].

Regarding longer treatment, the available data clearly

show that bisacodyl and sodium picosulfate as used both

in controlled trials and in open observations do not have

untoward effects on the electrolyte balance. This holds

true for trials over four weeks and for observations over

years and decades. On one hand, this is not surprising

since laxatives should be used by constipated patients in

doses not leading to diarrhea but to a soft formed stool.

However, as reported in nearly all trials with laxatives

diarrhea sometimes does occur although not intended.

This is reflected in the recent trials with bisacodyl and

sodium picosulfate, respectively, where patients were

allowed to lower the daily dose [14,15]. The fact that

about half of the patients on verum did so suggests some

diarrhea occurring with the full dose. However, these

days were obviously irrelevant with regard to serum

electrolytes.

Can the compliance with the dose be extrapolated

from controlled trials to the real life situation? From an

observational study in constipated patients taking sodium

picosulfate, it is known that nearly all users adhere to the

recommendation regarding interval of intake and dose

[18]. This makes it highly unlikely that the use of di-

phenyl methanes in daily practice will expose the users at

risk for electrolyte losses.

In summary, there is not only no indication that chro-

nic use of diphenyl methanes in recommended doses

may lead to electrolyte imbalance, particularly hypo kale-

mia, but controlled trials have specifically refuted this

side effect.

REFERENCES

[1] Binder, H.J. and Donowitz, M. (1975) A new look at

laxative action. Gastroenterology, 69, 1001-1005.

[2] Hervé, S., Savoye, G., Behbahani, A., Leroi, A.M., Denis,

P. and Ducrotté, P. (2004) Results of 24-h manometric

S. Müller-Lissner / Open Journal of Gastroenterology 3 (2013) 272-275 275

recording of colonic motor activity with endoluminal in-

stillation of bisacodyl in patients with severe chronic slow

transit constipation. Neurogastroenterology and Motility,

16, 397-402. doi:10 .1111/j.1365-2982.2004.00535.x

[3] Bundesvereinigung Deutscher Apothekerverbände, 2011.

http://www.abda.de/52+B6JmNIYXNoPTMy MjllYmNh

MTQmdHhfdHRuZXdzW2JhY2tQaWRdPTI0JnR4X3R

0bmV3c1twb2ludGVyXT01JnR4X3R0bmV3c1t0dF9uZ

XdzXT0xMzU4.html

[4] ADRAC (2002) Electrolyte disturbances with sodium

picosulfate bowel cleansing products. Australian Adverse

Drug Reactions Bulletin, 21, 1-4.

[5] (1997) Consumer reports complete drug reference, 981-

988.

[6] Fruit-Eze, Inc. Laxative Warnings, Side Effects & Con-

traindications Reported in Medical Literature.

http://web.pdx.edu/~sujata/FruitEze/education/laxative/m

edical_warnings.html#1

[7] Bytzer, P., Stokholm, M., Andersen, I., Klitgaard, N.A.

and Schaffalitzky de Muckadell, O.B. (1989) Prevalence

of surreptitious laxative abuse in patients with diarrhoea

of uncertain origin: A cost benefit analysis of a screening

procedure. Gut, 30, 1379-1384.

doi:10.1136/gut.30.10.1379

[8] Cummings, J.H., Sl ade n, G.E. , James, O.F. W. , Sarner, M.

and Misiewicz, J.J. (1974) Laxative-induced diarrhoea: A

continuing clinical problem. British Medical Journal, 1,

537. doi:10.1136/bmj.1.5907.537

[9] Read, N.W., Krejs, G.J. and Read, M.G. (1980) Chronic

diarrhea of unknown origin. Gastroenterology, 78, 264-

271.

[10] Ruidisch, M.H., Hutt, H.-J. and König, E. (1994) Laxan-

zien-langzeittherapie mit bisacodyl. Wirksamkeit und ver-

träglichkeit bei patienten mit rückenmarkverletzungen.

Ärztliche Forschung, 41, 3-8.

[11] Longstreth, G.F., Thompson, W.G., Chey, W.D., Hough-

ton, L.A., Mearin, F. and Spiller, R.C. (2006) Functional

bowel disorders. Gastroenterology, 130, 1480-1491.

doi:10.1053/j.gastro.2005.11.061

[12] Thompson, W.G., Longstreth, G.F., Drossman, D.A.,

Heaton, K.W., Irvine, E.J. and Müller-Lissner, S.A. (1999)

Functional bowel disorders and functional abdominal

pain. Gut, 45, II43-II47. doi:10.1136/gut.45.2008.ii43

[13] Kienzle-Horn, S., Vix, J.M., Schuijt, C., Peil, H., Jordan,

C.C. and Kamm, M.A. (2007) Comparison of bisacodyl

and sodium picosulfate in the treatment of chronic con-

stipation. Current Medical Research and Opinion, 23,

891-899. doi:10.1185/030079907X178865

[14] Kamm, M.A., Mueller-Lissner, S., Wald, A., Richter, E.,

Swallow, R. and Gessner, U. (2011) Oral bisacodyl is ef-

fective and well-tolerated in patients with chronic consti-

pation. Clinical Gastroenterology and Hepatology, 9,

577-583. doi:10.1016/j.cgh.2011.03.026

[15] Müller-Lissner, S.A., Kamm, M.A., Scarpignato, C. and

Wald, A. (2005) Myths and misconceptions about chronic

constipation. American Journal of Gastroenterology, 100,

232-242. doi:10.1111/j.1572-0241.2005.40885.x

[16] Müller-Lissner, S.A. (1996) What has happened to the

cathartic colon? Gut, 39, 486-488.

doi:10.1136/gut.39.3.486

[17] Kienzle-Horn, S., Vix, J.M., Schuijt, C., Peil, H., Jordan,

C.C. and Kamm, M.A. (2006) Efficacy and safety of bis-

acodyl in the acute treatment of constipation: A double-

blind, randomized, placebo-controlled study. Alimentary

Pharmacology & Therapeutics, 23, 1479-1488.

doi:10 .1111/j.1365-2036.2006.02903.x

[18] Hinkel, U., Schuijt, C. and Erckenbrecht, J. (2008) OTC

laxative use of sodium picosulfate—Results of a phar-

macy-based patient survey (cohort study). International

Journal of Clinical Pharmacology and Therapeutics, 46,

89-95.